Osteoporosis screening in people with airways disease.

We tested associations between risk factors and bone mineral density in airways disease subjects, and developed a clinical screening tool to identify people who could benefit from bone mineral density testing. Subjects were recruited through hospital outpatients and pharmacies (Newcastle, n = 172). With survey refinement, we then tested a revised tool in a second sample (Adelaide, n = 317). Study factors included oral/inhaled corticosteroid use, asthma severity, respiratory admissions, physical activity, percent predicted forced expiratory volume in one second (FEV1), body mass index, and smoking history. Outcomes were bone mineral density of lumbar vertebra (L2-4) and total (or neck of) femur. Analysis was logistic regression with generation of a simple screening algorithm based upon coefficients. Scoring algorithm risk factors for T-score of < - 2.0: age > or = 68 = 10 points, bone mineral density < 20 = 25, weight < 60 kg = 20, 60-69 kg = 10, > or = 80 cigarette pack years = 15, low-level leisure activity = 5, area under receiver operator curve 0.83. For a cut-off score of 10, sensitivity was 91.2%, specificity 53.9%, positive and negative predictive values 52.3 and 91.7%, and 67.2% were correctly classified. In conclusions, our model has acceptable sensitivity, although limited specificity. Use of this tool may reduce unnecessary referrals for bone mineral density measurement.

Randomized controlled trial of alendronate in airways disease and low bone mineral density.

BACKGROUND: Patients with airways disease have been demonstrated to be at risk of osteoporosis, and this is likely to be multifactorial. Our aim was to identify patients with low bone mineral density (BMD) using a screening program, and then evaluate the benefit of daily alendronate. METHOD: Subjects with hip or lumbar spine baseline T-scores < - 2.5, or Z-score < - 1.0 commenced on alendronate/calcium (10 mg/600 mg day) or placebo/calcium, in a double blind randomized controlled trial. BMD by dual emission X-ray absorptiometry (lumbar vertebrae 2-4, neck of femur, total femur) was repeated after 12 months, with adverse events recorded. RESULTS: 145 subjects (74 male, 71 female, mean age 67, median FEV1 1.0 litres = 43% of predicted) were enrolled; 66 alendronate/calcium, 79 placebo/calcium with 24 and 26 withdrawals, respectively. Per protocol but not intention to treat analysis of covariance demonstrated statistically significant improvements in T and Z scores for lumbar spine bone mineral density (P = 0.035, P = 0.040), with no improvement demonstrated at the hip. CONCLUSIONS: Improvement in bone mineral density has been demonstrated at the lumbar spine, but not hip, by per protocol analysis, with daily alendronate, at 12 months.

Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment.

BACKGROUND: Scleroderma renal crisis (SRC) is a rare but feared complication of scleroderma. Angiotensin--converting enzyme (ACE) inhibition has significantly improved survival, but it is unknown whether prophylactic ACE inhibitors will prevent this complication. AIMS: To determine: (i) the frequency of SRC in our cohort of well-characterized scleroderma patients resident in South Australia, (ii) any predisposing clinical and serological features, (iii) median disease duration at which SRC occurs, (iv) possible precipitants, (v) disease outcome, and (vi) whether patients were taking ACE inhibitors prior to onset of SRC. METHODS: Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register. RESULTS: SRC occurred in 16 patients. This constituted 2.8% of a total scleroderma cohort and 15% of the diffuse scleroderma cohort identified in South Australia. All 16 patients had diffuse cutaneous scleroderma. SRC occurred at a median disease duration of 15 months (range 1 week-11 years). Disease outcome was poor (five deaths, three requiring long-term dialysis and only two patients regaining a normal creatinine) despite aggressive antihypertensive treatment (including ACE inhibitors) in an intensive care or specialized renal unit. Two patients were later able to discontinue dialysis. Only two patients were taking small doses of ACE inhibitors prior to the onset of their SRC. The frequency of Scl-70 was decreased in the SRC group (P = 0.003). CONCLUSION: SRC is a rare event occurring in a small proportion of patients with diffuse scleroderma. The outcome of SRC was poor despite aggressive antihypertensive treatment. It is hypothesized that prophylactic ACE inhibition in susceptible patients might prevent or ameliorate this complication.

Immunoglobulin kappa light chain gene alleles are not associated with primary Sjögren's syndrome.

The immunoglobulin kappa (Km) light chain gene is polymorphic and is believed to play a role in the pathology of infectious and autoimmune diseases. Polymorphisms within the constant region of the Km gene encode three alleles designated Km1, Km1,2 and Km3. Previous studies using serological detection of Km allotypes reported associations between specific Km allotypes, systemic lupus erythematosus and the presence of anti-La antibodies, yet these findings were not confirmed in other studies. In order to more precisely define any associations between Km alleles and anti-Ro/La antibodies we used the polymerase chain reaction and restriction fragment length polymorphisms for Km genotyping in a large cohort of patients with primary Sjögren's syndrome (SS). No associations were observed between specific Km alleles and primary SS when compared with a control population, nor within serologically defined subsets of SS patients. We conclude that Km alleles are not associated with primary SS or the Ro/La autoantibody response.

Serum interleukin-6 and thyroid hormones in rheumatoid arthritis.

Using rheumatoid arthritis (RA) as a model, we have investigated whether the activation of the cytokine system, in particular, activation of interleukin (IL)-6 production, is a major cause of the depressed serum T(3) seen frequently in the nonthyroidal illness syndrome (NTIS). RA was chosen because it is a chronic autoimmune disease leading to increased serum IL-6 concentrations. We studied 16 untreated RA and 35 treated RA patients. Twenty-seven treated and 27 untreated patients with noninflammatory musculoskeletal symptoms served as controls. The patient groups displayed similar age distribution and nutritional status. Untreated RA patients displayed elevations of serum IL-6 (mean, 37.5 pg/mL) and C-reactive protein (CRP; mean, 41.3 mg/L), consistent with the inflammatory nature of their disease. Treated RA patients had significantly reduced serum IL-6 (mean, 9.9 pg/mL) and CRP (mean, 13.3 mg/L) compared with untreated RA patients, while untreated and treated patients with noninflammatory musculoskeletal symptoms had near normal serum IL-6 (mean, 2.5, 6.6 pg/mL, respectively) and CRP levels (mean, 5.8, 8.1 mg/L, respectively). However, there were no significant differences in serum concentrations of free T(3) (FT(3)) and free T(4) (FT(4)) between groups, and thyroid indices were in the normal range in RA patients. Moreover, no significant correlations between serum concentration of IL-6 and any of the thyroid hormones were demonstrated for any of the patient groups. In conclusion, we have been unable to confirm in RA that IL-6 activation leads to the low T(3) state of NTIS.

Evaluation of hand function in patients undergoing long term haemodialysis.

OBJECTIVE: Haemodialysis is associated with the deposition of beta(2) microglobulin in musculoskeletal structures, leading to the syndrome of dialysis related amyloidosis and impairment of hand function. This study aimed at assessing hand function using the Sollerman test in a cross section of patients undergoing haemodialysis. METHODS: Recipients of haemodialysis underwent the Sollerman test of hand grip function, which assesses 20 activities of daily living using eight grip types, and the JAMAR grip strength test, visual analogue scales (VAS) for pain (VAS-P) and function (VAS-F), and Health Assessment Questionnaire (HAQ) were determined. Results-Thirty five subjects (26 male), with mean age 53.2 years, participated. The average duration of haemodialysis was 6.2 years (range one month to 25 years). The median Sollerman score was 77, with 19/35 (54%) patients receiving haemodialysis having a score below the lower normal value of 78-80. The log Sollerman score correlated poorly with age (rs=0.16, p=0.35), and significantly with the HAQ score (r(s)=-0.66, p<0.00005), duration of haemodialysis (rs=-0.39, p<0.05), VAS-F (rs=-0.41, p<0.05), VAS-P (rs=-0.34, p<0.05), and JAMAR score (rs=0.57, p<0.05). Sollerman scores were highly correlated between dominant and non-dominant hands (rs=0.69, p<000005). CONCLUSIONS: Hand dysfunction is a common finding among patients undergoing long term haemodialysis. The Sollerman test accurately reflects patient function as measured by HAQ, VAS-F, and grip strength, but less so pain. Its use for the early detection of dialysis related amyloidosis and in the serial monitoring of the effects of hand treatment programmes is encouraged.

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins >90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami.

OBJECTIVE: To determine whether regional cerebral blood flow (rCBF) is abnormal in any cerebral structure of women with fibromyalgia (FM), following a report that rCBF is reduced in the thalami and heads of caudate nuclei in FM. METHODS: Seventeen women with FM and 22 healthy women had a resting single-photon-emission computed tomography (SPECT) brain scan to assess rCBF and a T1-weighted magnetic resonance imaging (MRI) scan to enable precise anatomic localization. Additionally, all participants underwent 2 manual tender point examinations and completed a set of questionnaires evaluating clinical features. SPECT scans were analyzed for differences in rCBF between groups using statistical parametric mapping (SPM) and regions of interest (ROIs) manually drawn on coregistered MRI. RESULTS: Compared with control subjects, the rCBF in FM patients was significantly reduced in the right thalamus (P = 0.006), but not in the left thalamus or head of either caudate nucleus. SPM analysis indicated a statistically significant reduction in rCBF in the inferior pontine tegmentum (corrected P = 0.006 at the cluster level and corrected P = 0.023 for voxel of maximal significance), with consistent findings from ROI analysis (P = 0.003). SPM also detected a reduction in rCBF on the perimeter of the right lentiform nucleus. No correlations were found with clinical features or indices of pain threshold. CONCLUSION: Our finding of a reduction in thalamic rCBF is consistent with findings of functional brain imaging studies of other chronic clinical pain syndromes, while our finding of reduced pontine tegmental rCBF is new. The pathophysiologic significance of these changes in FM remains to be elucidated.

Validation of fully automatic brain SPET to MR co-registration.

Fully automatic co-registration of functional to anatomical brain images using information intrinsic to the scans has been validated in a clinical setting for positron emission tomography (PET), but not for single-photon emission tomography (SPET). In this paper we evaluate technetium-99m hexamethylpropylene amine oxime to magnetic resonance (MR) co-registration for five fully automatic methods. We attached six small fiducial markers, visible in both SPET and MR, to the skin of 13 subjects. No increase in the radius of SPET acquisition was necessary. Distortion of the fiducial marker distribution observed in the SPET and MR studies was characterised by a measure independent of registration and three subjects were excluded on the basis of excessive distortion. The location of each fiducial marker was determined in each modality to sub-pixel precision and the inter-modality distance was averaged over all markers to give a fiducial registration error (FRE). The component of FRE excluding the variability inherent in the validation method was estimated by computing the error transformation between the arrays of MR marker locations and registered SPET marker locations. When applied to the fiducial marker locations this yielded the surface registration error (SRE), and when applied to a representative set of locations within the brain it yielded the intrinsic registration error (IRE). For the best method, mean IRE was 1.2 mm, SRE 1.5 mm and FRE 2.4 mm (with corresponding maxima of 3.3, 4.3 and 5.0 mm). All methods yielded a mean IRE <3 mm. The accuracy of the most accurate fully automatic SPET to MR co-registration was comparable with that published for PET to MR. With high standards of calibration and instrumentation, intra-subject cerebral SPET to MR registration accuracy of <2 mm is attainable.

The clinical associations of mitotic spindle autoantibodies in a South Australian cohort.

BACKGROUND: The mitotic spindle apparatus (MSA) is a unique structure of microtubules and associated proteins involved in the segregation and reorganisation of chromosomes during cell division. Autoantibodies to the MSA (anti-MSA) are reported to occur rarely, but are easily identified during the immunofluorescent detection of anti-nuclear antibodies (ANA), and are generally reported as part of that investigation. AIMS: As the clinical significance of these antibodies is unknown, our aim was to identify the clinical features of subjects identified with anti-MSA, and in a subset investigate the co-association with organ specific anti-thyroid antibodies. METHODS: All ANA results from the three major immunology laboratories serving South Australia between January 1993 and June 1998 were retrospectively reviewed to identify anti-MSA subjects. Clinical details were extracted from hospital or general practice records using a standard proforma. Thyroid autoantibodies were measured using standard technique. A control group of consecutive ANA positive, anti-MSA negative individuals had anti-thyroid antibodies measured. Statistical comparison used chi2 test. RESULTS: Fifty-five subjects (43F) were identified with mean age 59.8 (range 17-91); 39 had specific diagnoses, with 16 identified as part of non-specific investigations. 'Arthritis' broadly accounted for the largest group, transient inflammatory arthritis n=7, degenerative joint disease n=6, rheumatoid arthritis n=5. Adenocarcinoma and mesothelioma accounted for one case each. Thirty-two subjects had anti-thyroid antibodies tested, with ten of 21 and two of 11 positive among the groups with anti-MSA titre >1:80 and <1:40 respectively, chi2=2.7, p=0.1. Anti-thyroid antibodies were detected more frequently among the high titre anti-MSA group (ten of 21) compared with high titre positive ANA, negative anti-MSA group (two of 11), RRisk 4.4, chi2=5.34, p=0.02. CONCLUSION: This study confirmed the relative rarity of anti-MSA and that its association is primarily with rheumatic diseases. The coincidence of mesothelioma is novel with only two previous reports of malignancy and anti-MSA. The co-association of high titre anti-MSA and thyroid autoantibodies suggest that the latter should be a follow up investigation if the former is identified as part of an investigative screen.

Evaluation of antibodies to beta2-glycoprotein 1 in the causation of coronary atherosclerosis as part of the antiphospholipid syndrome.

BACKGROUND: Anticardiolipin antibodies (aCL) are associated with accelerated coronary atherosclerosis. Beta2-glycoprotein 1 is a cofactor necessary for the binding of aCL. AIM: The aim of this study was to determine whether antibodies to beta2-glycoprotein 1 (anti-beta2GP1) predispose to coronary artery disease (CAD), and whether the measurement of anti-beta2GP1 will be more useful than aCL alone in the evaluation of coronary risk. METHODS: Persons who had undergone coronary angiography were invited to participate, and risk factors for coronary atherosclerosis recorded. IgG aCL and anti-beta2GP1 were measured and fasting triglyceride (TG) and total cholesterol (TC) levels were determined. Angiographic score (AS) was defined as the number of diseased vessels (0, 1, 2, 3), (>50% stenosis). Ethics Committee approval was obtained. Statistical comparison used the Student's t test and Chi-squared test. RESULTS: Ninety-seven subjects (63 male) with age range 38-81 years (mean 66.0) participated. There were 31 subjects with AS=0, 27 with AS=1, 22 with AS=2, and 17 with AS=3. The three subjects with positive aCL all had CAD, as did three of the four subjects with positive anti-beta2GP1. Among patients with CAD, there was an equal incidence (4.5%, three/66) of aCL and anti-beta2GP1, and an incidence of either aCL or anti-beta2GP1 of 7.6% (five/66). Compared to the group with AS=0, those with AS=1, 2 or 3 comprised a higher mean age (p=0.001) however, there was no significant difference in the prevalence of other coronary risk factors between the two groups. There was no difference in the proportions of patients with either aCL or anti-beta2GP1 in the group with AS=1, 2, or 3, compared to the group with AS=0 (5/66 c.f. 1/31, chi2=0.146, p>0.5). CONCLUSIONS: Our study has not supported an association between anti-beta2GP1 and CAD. The measurement of anti-beta2GP1 (or aCL) in the investigation of premature CAD is not justified on the basis of our results.

South Australian Scleroderma Register: analysis of deceased patients.

The demographic, clinical, pathological and serological features of 123 decreased patients with systemic sclerosis have been analysed. These patients consisted of all identified patients dying with this disease in South Australia between 1983 and 1996 inclusive. There were 85 females and 38 males, with the ratio of limited:diffuse:overlap disease subset being 9:5:1. Disease characteristics revealed that patients with the limited disease tended to be female with high frequencies of the centromere autoantibody, while patients with the diffuse disease had equal gender representation with the frequent presence of nucleolar, speckled or homogeneous antinuclear antibody. Mean duration of disease and mean age of death for the limited:diffuse:overlap subsets differed significantly between groups (p < 0.05) and were 16.5, 9.3 and 10.9 years and 71.9, 57.8 and 52.8 years respectively. Cumulative survival curves for the subsets differed highly significantly, with patients with the limited diseases dying more commonly from right heart failure (documented terminally in 25% of the centromere positive limited subset), cardiovascular disease or cancer, while patients with the diffuse subset died from respiratory failure, renal failure or cardiovascular disease. In conclusion, this retrospective analysis has revealed that scleroderma is a relatively common but clinically heterogeneous disorder. There are important clinical and prognostic implications in defining limited versus diffuse versus overlap disease.

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis.

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda > or = 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

A genome-wide screen for susceptibility loci in ankylosing spondylitis.

OBJECTIVE: To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). METHODS: One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. RESULTS: When only the MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. CONCLUSION: The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.